Cao L, Wu J, Gardner D G
Metabolic Research Unit, University of California, San Francisco 94143, USA.
J Biol Chem. 1995 Oct 20;270(42):24891-7. doi: 10.1074/jbc.270.42.24891.
Atrial natriuretic peptide (ANP) treatment of rat aortic smooth muscle cells suppressed both 125I-ANP binding and ANP-dependent cGMP accumulation, suggesting reductions in the type C (NPR-C) and type A (NPR-A) natriuretic peptide receptor populations, respectively. NPR-A, but not NPR-C, mRNA levels were reduced in a dose-dependent fashion by ANP. The latter effect appeared to be due, at least in part, to suppression of NPR-A gene promoter activity. ANP effected a dose- and time-dependent reduction in a transiently transfected NPR-A luciferase reporter (-1575LUC). Analysis of 5' deletion mutants of the NPR-A promoter demonstrated that the ANP-dependent sequence lies between -1575 and -1290 relative to the transcription start site. Inhibition of the ANP promoter was also effected by brain natriuretic peptide, type C natriuretic peptide, and 8-bromo-cGMP, but not by the NPR-C-selective ligand cANF. In the case of 8-bromo-cGMP, the responsive element(s) was localized to the same 285-base pair region linked to the ANP effect above. These findings indicate that ANP autoregulates its own receptors in these cells and, at least in the case of NPR-A, it does so through suppression of receptor gene expression and receptor synthesis. This suppression may operate through a cGMP-dependent element located more than a kilobase upstream from the transcription start site.
心房利钠肽（ANP）对大鼠主动脉平滑肌细胞的处理抑制了125I-ANP结合以及ANP依赖的cGMP积累，分别提示C型（NPR-C）和A型（NPR-A）利钠肽受体数量减少。ANP以剂量依赖方式降低NPR-A而非NPR-C的mRNA水平。后一种效应似乎至少部分归因于NPR-A基因启动子活性的抑制。ANP对瞬时转染的NPR-A荧光素酶报告基因（-1575LUC）产生剂量和时间依赖性的降低作用。对NPR-A启动子的5'缺失突变体分析表明，ANP依赖序列位于相对于转录起始位点的-1575至-1290之间。脑利钠肽、C型利钠肽和8-溴-cGMP也能抑制ANP启动子，但NPR-C选择性配体cANF则不能。就8-溴-cGMP而言，反应元件定位于与上述ANP效应相关的相同285碱基对区域。这些发现表明，ANP在这些细胞中对其自身受体进行自动调节，并且至少就NPR-A而言，它是通过抑制受体基因表达和受体合成来实现的。这种抑制可能通过位于转录起始位点上游超过1千碱基处的cGMP依赖元件起作用。
